Biomedical subjects

Cesare Danesino

Publications and source records attributed to Cesare Danesino.

At least 19 recordsLinked to original sources

PubMed2007

Townes-Brocks syndrome: twenty novel SALL1 mutations in sporadic and familial cases and refinement of the SALL1 hot spot region.

Townes-Brocks syndrome (TBS) is an autosomal dominant malformation syndrome characterized by renal, anal, ear, and thumb anomalies caused by SALL1 mutations. To date, 36 SALL1 mutations have been described in TBS patients. All but three of those, namely p.R276X, p.S372X, and c.1404dupG, have been found only in single families thereby preventing phenotype-genotype correlations. Here we present 20 novel mutations (12 short deletions, five short duplications, three nonsense mutations) in 20 unrelated families. We delineate the phenotypes and report previously unknown ocular manifestations, i.e. congenital cataracts with unilateral microphthalmia. We show that 46 out of the now 56 SALL1 mutations are located between the coding regions for the glutamine-rich domain mediating SALL protein interactions and 65 bp 3' of the coding region for the first double zinc finger domain, narrowing the SALL1 mutational hotspot region to a stretch of 802 bp within exon 2. Of note, only two SALL1 mutations would result in truncated proteins without the glutamine-rich domain, one of which is reported here. The latter is associated with anal, ear, hand, and renal manifestations, indicating that the glutamine-rich domain is not required for typical TBS.

Abnormalities, Multiple↗

PubMed2007

Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French-Italian HHT network.

PURPOSE: Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by arteriovenous malformations (AVM), mostly cutaneous and mucous (telangiectases), but also involving the lungs (PAVM), liver (HAVM) and brain (CAVM). We studied the relationship between the phenotype and genotype in patients with a proven mutation in either ENG (HHT1) or ACVRL1 (HHT2). METHODS: Clinical features and their age of onset were compared between HHT1 and HHT2. The type of mutation was also analyzed. Clinical manifestations were distinguished from lesions found by screening. RESULTS: Ninety-three HHT1 patients and 250 HHT2 patients were included. Epistaxis occurred later in HHT2, with incomplete penetrance (P<0.0001). Symptomatic PAVMs were more frequent in HHT1 (34.4 vs. 5.2%, P<0.001), as were cerebral abscesses (7.5 vs. 0.8%, P=0.002). Gastrointestinal bleeding occurred more frequently in HHT2 (16.4 vs. 6.5%, P=0.017). Symptomatic hepatic involvement was only seen in HHT2 patients. PAVMs were more frequently detected in asymptomatic HHT1 patients (54 vs. 12.8%, P<0.0001). PAVMs and HAVMs were often family clustered in HHT1 and HHT2, respectively. Truncating mutations were associated with a higher frequency of epistaxis and telangiectasis, in HHT2. CONCLUSION: This study shows major differences between HHT1 and HHT2 phenotypes, which should be taken into account for future clinical studies.

Activin Receptors, Type II↗

PubMed2006

Dietary treatment in adult-onset type II glycogenosis.

Eight patients with adult-onset type II glycogenosis (GSD II), all carrying the IVS1-13T<G mutation, were treated with high-protein isocaloric diet for 3 years. We evaluated the usefulness of this approach through the assessment of the skeletal muscles (by manual muscle testing, quantitative isokinetic exercise, and muscle MRI) and the respiratory function (by spirometry). Three patients with mild or moderate disease severity refused the diet and were still monitored for comparison: they showed clinical (2 patients) or clinicoradiological (1 patient) progression of muscle weakness, while respiratory function remained unchanged. Among the patients accepting the dietary treatment, muscle strength remained unchanged, as did the degree of fatty infiltration and atrophy as assessed by muscle MRI; respiratory function worsened in 2/5 patients with severe baseline respiratory dysfunction. High-protein diet may stabilize disease progression at the skeletal muscles, but does not produce significant clinical improvements; moreover, the usefulness of this approach in patients with severe respiratory disease seems questionable.

Adult↗

PubMed2006

Variations of the perforin gene in patients with autoimmunity/lymphoproliferation and defective Fas function.

Mutations decreasing function of the Fas death receptor cause the autoimmune lymphoproliferative syndrome (ALPS) with autoimmune manifestations, spleen/lymph node enlargement, and expansion of CD4/CD8-negative T cells. Dianzani Autoimmune Lymphoproliferative Disease (DALD) is a variant lacking this expansion. Perforin is involved in cell-mediated cytotoxicity and its biallelic mutations cause familial hemophagocytic lymphohistiocytosis (HLH). We previously described an ALPS patient carrying heterozygous mutations of the Fas and perforin genes and suggested that they concurred in ALPS. This work extends the analysis to 14 ALPS, 28 DALD, and 816 controls, and detects an N252S amino acid substitution in 2 ALPS, and an A91V amino acid substitution in 6 DALD. N252S conferred an OR = 62.7 (P = .0016) for ALPS and A91V conferred an OR = 3 (P = .016) for DALD. Copresence of A91V and variations of the osteopontin gene previously associated with DALD conferred an OR = 17 (P = .0007) for DALD. In one N252S patient, NK activity was strikingly defective in early childhood, but became normal in late childhood. A91V patients displayed lower NK activity than controls. These data suggest that perforin variations are a susceptibility factor for ALPS/DALD development in subjects with defective Fas function and may influence disease expression.

Amino Acid Substitution↗

PubMed2006

Delineation of the ADULT syndrome phenotype due to arginine 298 mutations of the p63 gene.

The ADULT syndrome (Acro-Dermato-Ungual-Lacrimal-Tooth, OMIM 103285) is a rare ectodermal dysplasia associated with limb malformations and caused by heterozygous mutations in p63. ADULT syndrome has clinical overlap with other p63 mutation syndromes, such as EEC (OMIM 604292), LMS (OMIM 603543), AEC (106260), RHS (129400) and SHFM4 (605289). ADULT syndrome characteristics are ectrodactyly, ectodermal dysplasia, mammary gland hypoplasia and normal lip and palate. The latter findings allow differentiation from EEC syndrome. LMS differs by milder ectodermal involvement. Here, we report three new unrelated ADULT syndrome families, all with mutations of arginine 298. On basis of 16 patients in five families with R298 mutation, we delineate the ADULT syndrome phenotype. In addition, we have documented a gain-of-function effect on the dNp63gamma isoform caused by this mutation. We discuss the possible relevance of oral squamous cell carcinoma in one patient, who carries this p63 germline mutation.

Abnormalities, Multiple↗

PubMed2006

Shwachman syndrome as mutator phenotype responsible for myeloid dysplasia/neoplasia through karyotype instability and chromosomes 7 and 20 anomalies.

An investigation of 14 patients with Shwachman syndrome (SS), using standard and molecular cytogenetic methods and molecular genetic techniques, showed that (1) the i(7)(q10) is not, or not always, an isochromosome but may arise from a more complex mechanism, retaining part of the short arm; (2) the i(7)(q10) has no preferential parental origin; (3) clonal chromosome changes, such as chromosome 7 anomalies and del(20)(q11), may be present in the bone marrow (BM) for a long time without progressing to myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML); (4) the del(20)(q11) involves the minimal region of deletion typical of MDS/AML; (5) the rate of chromosome breaks is not significantly higher than in controls, from which it is concluded that SS should not be considered a breakage syndrome; (6) a specific kind of karyotype instability is present in SS, with chromosome changes possibly found in single cells or small clones, often affecting chromosomes 7 and 20, in the BM. Hence, we have confirmed our previous hypothesis that the SS mutation itself implies a mutator effect that is responsible for MDS/AML through these specific chromosome anomalies. This conclusion supports the practice of including cytogenetic monitoring in the follow-up of SS patients.

Abnormalities, Multiple↗

PubMed2006

Echocardiographic screening discloses increased values of pulmonary artery systolic pressure in 9 of 68 unselected patients affected with hereditary hemorrhagic telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by the presence of telangiectases and arteriovenous malformations. In some families in whom a form of idiopathic pulmonary arterial hypertension cosegregated with HHT, mutations in the ACVRL1 gene were present. PURPOSE: We noninvasively measured the pulmonary artery systolic pressure (PASP) in a group of patients with HHT. METHODS: Doppler transthoracic echocardiography and mutation analysis by direct sequencing were used. RESULTS: We studied 68 patients (age 19-84 years, mean 50.75 + 15.11; 32 females) and PASP measurement was possible in 44 (64. 7%); in addition, 9 of them (20.5%) showed elevated values. Molecular analysis identified mutations in the ACVRL1 gene in 7 of these 9 subjects. Even on exclusion of relatives of the single case with known pulmonary hypertension, 5 of 37 patients (13.5%) still showed values higher than those of controls. CONCLUSION: The data indicate that elevated PASP values are a frequent and previously unrecognized complication of HHT. Because clinically significant pulmonary artery hypertension (a relevant cause of morbidity and mortality) may subsequently develop in these patients, we propose that the measurement of PASP should be included among the parameters recorded for all patients undergoing Doppler transthoracic echocardiography during routine clinical screening.

Activin Receptors, Type I↗

PubMed2006

Specific polymorphisms of cytokine genes are associated with different risks to develop single-system or multi-system childhood Langerhans cell histiocytosis.

Cytokines and chemokines determine mobilisation of Langerhans cells and their dysregulation is implicated in the pathogenesis of Langerhans cell histiocytosis (LCH). Twenty point mutations of 12 different cytokine genes were studied in 41 Italian children, 15 with single-system (SS) and 26 with multi-system disease. The allele and genotype distributions of interleukin-4 (IL-4) and interferon-gamma (IFNgamma) were significantly different in patients vs. 140 controls (P = 0.007, and P = 0.018). Older children with single-system disease shared the 'anti-inflammatory profile' determined by the intermediate producer genotype IFNgamma +874A/T (P = 0.029) and the high-producer genotypes IL-4 -590C/T and T/T (P = 0.029). Our findings suggest that specific cytokine gene variants affect susceptibility to LCH and its clinical heterogeneity.

Adolescent↗

PubMed2005

A proportion of patients with lymphoma may harbor mutations of the perforin gene.

Perforin mutations have been demonstrated in a proportion of patients diagnosed with the familial form of hemophagocytic lymphohistiocytosis (HLH). In the present study, we evaluated whether some patients with lymphoma sharing clinical characteristics with HLH might harbor mutations of the perforin gene. We analyzed 29 patients and found that 4 patients, who developed either Hodgkin or non-Hodgkin lymphoma, had biallelic mutations of the perforin gene. One of these 4 patients, a 19-year-old female with T-cell lymphoma, had a brother carrying the same mutations who developed HLH. In 2 of the 4 patients with biallelic mutations of the perforin gene, we evaluated perforin expression by flow cytometry and natural killer (NK) activity and both were found to be absent. Moreover, we documented the presence of monoallelic mutations of the perforin gene in 4 more patients. One of these 4 latter patients also carried a mutation of the Fas gene. These data indicate that perforin deficiency, either alone or in combination with other mutations of genes involved in lymphocyte survival or functional activity, may be present in patients with lymphoma. These findings suggest that perforin also plays a key role in the mechanisms of immune surveillance that prevent tumor growth and/or development.

Adolescent↗

PubMed2005

Facial erythema associated with short stature, absent distal phalanx, dental and nail anomalies: case report and neuropsychological profile.

We describe a patient presenting with a combination of dental agenesis, agenesis of the distal phalanx of the fifth finger, small, dystrophic toenails, permanent facial erythema, short stature and mild mental retardation. The neuropsychological profile of this patient which was studied in detail and showed a significant discrepancy between verbal and performance IQ. We discuss the differential diagnosis of this case and conclude that our patient's condition could represent a new syndrome.

Abnormalities, Multiple↗

PubMed2004

Inherited perforin and Fas mutations in a patient with autoimmune lymphoproliferative syndrome and lymphoma.

A 27-year-old man with the autoimmune lymphoproliferative syndrome and a large-B-cell lymphoma had heterozygous mutations in the Fas and perforin (Prf1) genes. The Fas mutation was inherited from his healthy father and was also carried by his healthy brother, whereas the Prf1 mutation was inherited from his healthy mother. The combined effect of the two mutant genes may have contributed to the development of the autoimmune lymphoproliferative syndrome and lymphoma in this patient.

Adult↗

PubMed2004

Growth hormone deficiency, anorectal agenesis, and brachycamptodactyly: a phenotype overlapping Stratton-Parker syndrome.

Stratton and Parker [1989] described a 17-month-old boy with the previously unreported combination of growth hormone (GH) deficiency, Wormian bones, mild developmental delay, brachycamptodactyly, heart defects, kidney hypoplasia, imperforate anus, bilateral cryptorchidism, and facial anomalies. A similar case was later reported by Gabrielli et al. [1994], who suggested the existence of a "Stratton-Parker syndrome." Here, we describe a boy with isolated GH deficiency, body asymmetry, and brachycamptodactyly. At birth, complete anorectal agenesis and cryptorchidism were detected, which required surgical treatment. Radiographic examination showed the presence of bilateral proximal radioulnar subluxation and Kirner anomaly. Brain MRI showed asymmetry of the posterior horns of the lateral ventricles and enlarged cisterna magna. Psychomotor development had been mildly delayed during the first years of life. Due to the unique association of GH deficiency with intestinal, genital, and limbs abnormalities, we believe that our patient may represent a further case of Stratton-Parker syndrome. All patients reported, till date, are sporadic males born to healthy nonconsanguineous parents. X-linked recessive inheritance is a possibility to consider.

Abnormalities, Multiple↗

PubMed2004

Smith-Magenis syndrome and growth hormone deficiency.

UNLABELLED: Smith-Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome including physical and neurobehavioural features. The disease is commonly associated with a ca. 3.7 Mb interstitial deletion of chromosome 17p11.2, while a 1.1 Mb critical region has been identified, containing about 20 genes expressed in multiple tissues. Haploinsufficiency of one of them, RAI1, seems to be responsible for the neurobehavioural, craniofacial and otolaryngological features of the syndrome, but not for short stature, commonly seen in SMS patients with chromosome deletion, implying the role of other genes in the 17p11.2 region. Growth failure is a final result of several different mechanisms involving decreased growth hormone (GH) production, reduced tissue response to GH, or impaired activity of epistatic factors. To our knowledge, the association of GH deficiency with SMS has never been reported and rarely investigated, despite the very short stature of SMS patients. We describe a girl with a full SMS phenotype and a typical 3.7 Mb deletion of 17p11.2 who also has GH deficiency. After starting replacement therapy, growth has significantly improved, her stature being now above both the 10th percentile and her genetic target. CONCLUSION: we suggest that an investigation of both growth hormone secretion and function is carried out in patients with Smith-Magenis syndrome and 17p11.2 deletion.

Abnormalities, Multiple↗

PubMed2004

Familial myelodysplastic syndromes, monosomy 7/trisomy 8, and mutator effects.

A family is reported, in which two sisters presented with myelodysplastic syndrome (MDS), namely refractory anemia with excess of blasts in transformation (RAEB-t), and refractory anemia (RA). Bone marrow chromosome changes were present in both: trisomy and tetrasomy 8 (with a pericentric inversion of one chromosome 8) in the older sister, and monosomy 7 (with clones with additional trisomies 19 and 21) in the younger one. Molecular data were obtained on the parental chromosome involved in these numerical anomalies, which proved to be of paternal origin in these cases. The observations of this family, and a review of familial cases of MDS/acute myeloid leukemia (AML), led us to consider that they may be divided into two groups: those which arise on the basis of a Mendelian predisposing disorder exerting a mutator effect, often with the acquisition of monosomy 7, and those in which no specific Mendelian predisposing disease is recognized, as the familial monosomy 7 cases and the one reported here. We postulate that in these families an inherited mutator effect is present and that it causes a karyotype instability, which leads to MDS/AML, often through the acquisition of monosomy 7 and trisomy 8.

Adolescent↗

PubMed2004

Familial platelet disorder with propensity to acute myelogenous leukemia: genetic heterogeneity and progression to leukemia via acquisition of clonal chromosome anomalies.

Familial platelet disorder with propensity to acute myelogenous leukemia, or FPD/AML (OMIM #601399), is a rare autosomal dominant condition, with only 12 families reported. It is characterized by qualitative and quantitative platelet defects and predisposition to the development of myeloid malignancies. Causal mutations have been identified in the RUNX1 gene (also known as AML1, CBFA2) in the 11 families so far analyzed. RUNX1 is a gene frequently involved in the pathogenesis of sporadic leukemia and myelodysplastic syndromes, through acquired chromosome rearrangements and point mutations. We report an Italian family with three members affected with FPD/AML, two sibs and their father, who developed myelodysplastic syndromes (which in one subsequently evolved into AML). Direct sequencing and polymorphisms haplotype analysis of the region of chromosome 21 where RUNX1 is mapped demonstrated that FPD/AML in this family was not caused by any mutation of the RUNX1 gene, thus providing evidence for the genetic heterogeneity of this disorder. Cytogenetic studies showed monosomy 7 in the marrow of all the three affected subjects, as well as an independent clone with trisomy 8 in the father. The importance of mutator effects in the pathogenesis of familial myeloid malignancies characterized by relevant chromosome changes, in the presence or absence of an underlying Mendelian disorder, has already been suggested. Our results and a review of the cytogenetic literature led us to postulate that mutations also causing FPD/AML may have a mutator effect that could give origin to myelodysplastic syndromes and acute myeloid leukemias through acquired chromosome changes.

Blood Platelet Disorders↗

PubMed2004

Muscle MRI in adult-onset acid maltase deficiency.

We report the spectrum of muscle involvement on magnetic resonance imaging in 11 patients with a molecularly confirmed diagnosis of adult-onset acid maltase deficiency at different clinical stages. Muscle magnetic resonance imaging showed a selective progressive pattern of muscle involvement with a constant involvement of the adductor magnus and semimembranosus at the early stage of the disease and a later fatty infiltration of the long head of the biceps femoris, semitendinosus and of the anterior thigh muscles. In the advanced phases a selective sparing of sartorius, rectus, and gracilis muscles and peripheral portions of the vastus lateralis was also evident. Muscle strength and magnetic resonance imaging findings were positively correlated. The results suggest that muscle magnetic resonance imaging may provide valuable diagnostic guidance for the assessment of accurate selective muscular involvement in acid maltase deficiency and may help monitor the progression of the disorder. Further control studies in a larger cohort are needed to evaluate the specificity of these findings.

Adult↗

PubMed2004

High prevalence of hepatic focal nodular hyperplasia in subjects with hereditary hemorrhagic telangiectasia.

A vascular pathogenesis of hepatic focal nodular hyperplasia (FNH) has been suggested; this study was aimed to evaluate in families with hereditary hemorrhagic telangiectasia (HHT) the prevalence of FNH, relating it to presence and stage of hepatic vascular malformations (VMs). Fifty-two HHT families underwent a screening program including abdominal Doppler sonography (US) searching for hepatic VMs; we classified them as minimal, moderate and severe, depending on the number and degree of abnormalities found by Doppler US. Presence of focal liver lesions was recorded. Diagnosis of FNH was made if at least two examinations, whether color Doppler US, liver scintigraphy, dynamic computed tomography (CT) or magnetic resonance (MR), showed suggestive findings. FNH was found in five out of 274 subjects (1.8%). All five were affected by HHT. Thus, percentage related to the group of affected patients increased to 2.9; 4/5 presented severe liver VMs. Female-to-male ratio was 4:1. FNH was single in three cases; tumor size ranged between 20 and 90 mm. During follow-up, no lesion showed a reduction in size, three showed an increase. Prevalence of FNH in patients with HHT is far greater than that reported in the general population; Doppler US role in its diagnosis and follow-up is highlighted.

Adolescent↗

PubMed2003

Clinical, genetic and immunologic analysis of a family affected by ozena.

Primary atrophic rhinitis is a chronic inflammation of the nasal mucosa characterized by atrophy of the mucous and bony tissue of the turbinates and by a thick, dense secretion, which quickly forms a characteristically fetid-smelling, greenish crust. We report the results of the clinical, genetic and immunologic investigations performed on eight subjects (three with ozena and five asymptomatic), members of the same familial group. The presence of the disease in the family fits well with dominant inheritance. All the culture specimens from the patients affected by ozena were positive for Klebsiella ozaenae, and one of them was also positive for Pseudomonas aeruginosa. All the three patients with ozena and two of the five apparently unaffected family members were positive for antinuclear antibodies. Immunoblotting showed a reactivity to a 50-kD protein, which was not identified by the common, recognized nuclear autoantigens. This was present in one of the three patients and three of the five other family members. Positivity for IgG-class anticardiolipins was correlated with disease manifestation in that it was found in two of the three patients and only in one of the five asymptomatic family members. The hypothesis of a genetic factor that could drive the chronicity of the inflammatory pattern of a pre-existing infectious nasal disease is suggested.

Adolescent↗